P53 in blind subterranean mole rats - Loss-of-function versus gain-of-function activities on newly cloned Spalax target genes

A. Avivi, O. Ashur-Fabian, A. Joel, L. Trakhtenbrot, K. Adamsky, I. Goldstein, N. Amariglio, G. Rechavi, E. Nevo

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


A tumor suppressor gene, p53, controls cellular responses to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and/or apoptosis. Recently, we demonstrated that in blind subterranean mole rats, Spalax, a model organism for hypoxia tolerance, the p53 DNA-binding domain contains a specific Arg174Lys amino acid substitution. This substitution reduces the p53 effect on the transcription of apoptosis genes (apaf1, puma, pten and noxa) and enhances it on human cell cycle arrest and p53 stabilization/homeostasis genes (mdm2, pten, p21 and cycG). In the current study, we cloned Spalax apaf1 promoter and mdm2 intronic regions containing consensus p53-responsive elements. We compared the Spalax-responsive elements to those of human, mouse and rat and investigated the transcriptional activity of Spalax and human Arg174Lys-mutated p53 on target genes of both species. Spalax and human-mutated p53 lost induction of apaf1 transcription, and increased induction of mdm2 transcription. We conclude that Spalax evolved hypoxia-adaptive mechanisms, analogous to the alterations acquired by cancer cells during tumor development, with a bias against apoptosis while favoring cell arrest and DNA repair.

Original languageEnglish
Pages (from-to)2507-2512
Number of pages6
Issue number17
StatePublished - 12 Apr 2007
Externally publishedYes

Bibliographical note

Funding Information:
We appreciate Dr Imad Shams help in this study, and we thank Eti Rosenthal for her technical assistance with the cell cycle experiments. We thank the Ancell Teicher Research Foundation for Genetics and Molecular Evolution for financial support. We also thank the Arison family for their donation to the Center of DNA Chips, Pediatric Oncology, Chaim Sheba Medical Center. GR holds the Djerassi Chair in Oncology at the Sackler School of Medicine.


  • Hypoxia
  • Subterranean mole rat
  • apaf1
  • mdm2
  • p53


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